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Rhodium-mediated [11C]Carbonylation: A library of N-phenyl-N′-{4-(4-quinolyloxy)-phenyl}-[11C]-urea derivatives as potential PET angiogenic probes
Hadassah/ Hebrew University Hospital, Jerusalem, Israel.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
Hadassah/ Hebrew University Hospital, Jerusalem, Israel.
2009 (English)In: Journal of labelled compounds & radiopharmaceuticals, ISSN 0362-4803, E-ISSN 1099-1344, Vol. 52, no 5, 151-157 p.Article in journal (Refereed) Published
Abstract [en]

As part of our ongoing investigation into the imaging of angiogenic processes, a small library of eight vascular endothelial growth factor receptor-2 (VEGFR-2)/platelet-derived growth factor receptor beta dual inhibitors based on the N-phenyl-N'-4-(4-quinolyloxy)-phenyl-urea was labelled with C-11 (beta(+), t(1/2) = 20.4 min) in the urea carbonyl position via rhodium-mediated carbonylative cross-coupling of an aryl azide and different anilines. The decay-corrected radiochemical yields of the isolated products were in the range of 38-81% calculated from [C-11]carbon monoxide. Starting with 10.7+/-0.5 GBq of [C-11]carbon monoxide, 1-[4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-3-(4-fluoro-phenyl)-[C-11]-urea (2.1 GBq) was isolated after total reaction time of 45 min with a specific activity of 92+/-4 GBq mu mol(-1).

Place, publisher, year, edition, pages
2009. Vol. 52, no 5, 151-157 p.
Keyword [en]
carbonylation, carbon-11, 11C, angiogenesis, VEGFR-2, PET, kinase
National Category
Organic Chemistry
Research subject
Organic Chemistry; Organic Pharmaceutical Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-98593DOI: 10.1002/jlcr.1582ISI: 000267243600003OAI: oai:DiVA.org:uu-98593DiVA: diva2:175149
Available from: 2009-02-27 Created: 2009-02-27 Last updated: 2017-12-13
In thesis
1. Design and Synthesis of 11C-Labelled Compound Libraries for the Molecular Imaging of EGFr, VEGFr-2, AT1 and AT2 Receptors: Transition-Metal Mediated Carbonylations Using [11C]Carbon Monoxide
Open this publication in new window or tab >>Design and Synthesis of 11C-Labelled Compound Libraries for the Molecular Imaging of EGFr, VEGFr-2, AT1 and AT2 Receptors: Transition-Metal Mediated Carbonylations Using [11C]Carbon Monoxide
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This work deals with radiochemistry and new approaches to develop novel PET tracers labelled with the radionuclide 11C.

Two methods for the synthesis of 11C-labelled acrylamides have been explored. First, [1-11C]-acrylic acid was obtained from a palladium(0)-mediated 11C-carboxylation of acetylene with [11C]carbon monoxide; this could be converted to the corresponding acyl chloride and then combined with benzylamine to form N-benzyl[carbonyl-11C]acrylamide. In the second method, the palladium(0)-mediated carbonylation of vinyl halides with [11C]carbon monoxide was explored. This latter method, yielded labelled acrylamides in a single step with retention of configuration at the C=C double bond, and required less amine compared to the acetylene method.

The vinyl halide method was used to synthesize a library of 11C-labelled EGFr-inhibitors in 7-61% decay corrected radiochemical yield via a combinatorial approach. The compounds were designed to target either the active or the inactive form of EGFr, following computational docking studies.

The rhodium(I)-mediated carbonylative cross-coupling of an azide and an amine was shown to be a very general reaction and was used to synthesize a library of dual VEGFr-2/PDGFrβ inhibitors that were 11C-labelled at the urea position in 38-78% dc rcy.

The angiotensin II AT1 receptor antagonist eprosartan was 11C-labelled at one of the carboxyl groups in one step using a palladium(0)-mediated carboxylation. Autoradiography shows specific binding in rat kidney, lung and adrenal cortex, and organ distribution shows a high accumulation in the intestines, kidneys and liver. Specific binding in frozen sections of human adrenal incidentalomas warrants further investigations of this tracer.

Three angiotensin II AT2 ligands were 11C-labelled at the amide group in a palladium(0)-mediated aminocarbonylation in 16-36% dc rcy. One of the compounds was evaluated using in vitro using autoradiography, and in vivo using organ distribution and animal PET. The compound was metabolized fast and excreted via urine. High radioactivity was also found in the liver, meaning that more metabolically stable compounds are desirable for future development.

 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 65 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 616
Keyword
[11C]carbon monoxide, isotopic labelling, PET, acrylamide, EGFR, VEGFR-2, 11C
National Category
Organic Chemistry
Research subject
Organic Chemistry; Organic Pharmaceutical Chemistry
Identifiers
urn:nbn:se:uu:diva-98599 (URN)978-91-554-7451-5 (ISBN)
Public defence
2009-04-17, BMC, B42, Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2009-03-26 Created: 2009-02-27 Last updated: 2012-08-03Bibliographically approved

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